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Author: Subject: Properties of diphenhydramine base?
OctanitroC
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[*] posted on 8-7-2014 at 15:28
Properties of diphenhydramine base?


Hello everybody, I was wondering if you could help me out with something. I'm performing an extraction of diphenhydramine from generic allergy pills; I crushed 76 pills, containing 1.9 g diphenhydramine HCl, and mixed the resulting powder with 200 mL of water to dissolve the hydrochloride. I then filtered off the supernatant to obtain 200 mL of a very faintly pink (from the pill coating), clear solution. I mixed this solution with an excess of NaOH solution, which caused the solution to immediately become cloudy. After this, I let the solution stand, but no separation occurred, so I added 20 g of NaCl to try to salt out the diphenhydramine base. This cleared the solution significantly and caused an oily liquid to come out of suspension and float on top of the solution. I'm not sure what this would be other than product, but I'm confused as to it being an oil. The (admittedly spotty) references I found all seemed to point to both the base and hydrochloride of diphenhydramine being solid at room temperature. Does anybody have a reference for the melting point of diphenhydramine in the base form, rather than the hydrochloride? I'd appreciate any help. Thanks!



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[*] posted on 8-7-2014 at 16:12


The melting point of the base (CAS# 58-73-1) is reported as 167C-172C (http://www.chemnet.com/cas/en/58-73-1/diphenhydramine.html).

[Edited on 9-7-2014 by Burner]




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[*] posted on 8-7-2014 at 20:41


Diphenylhydramine (CAS 58-73-1) is a liquid (bp 150-165 @ 2mm): See Merck Index 14th edition, 3309. Diphenylhydramine hydrochloride (CAS 147-24-0) has mp 166-170. So the oil you have is in all likelihood the desired freebase which you will need to isolate by extraction with a suitable solvent followed by an appropriate workup.

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9-7-2014 at 08:33
OctanitroC
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[*] posted on 9-7-2014 at 21:01


Alright, thanks! I lost quite a bit of the oil trying to pipette it out, so I'm re-running the extraction with 2.5 g of the hydrochloride. Will add the crude wet product to toluene and dry the toluene solution over anhydrous MgSO4, decant, then let the toluene evaporate off; that should eliminate water and water-soluble salts, etc. from the product.



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[*] posted on 10-7-2014 at 18:01


You need to be careful about evaporating your solvent in air as diphenylhydramine, being an amine, will absorb CO2 giving you a relatively useless solid. Do you have the means to gently distill off the toluene? Magnesium sulfate will not remove all the water whereas gentle distillation will via the azeotrope. A better drying agent would be solid sodium hydroxide followed by gentle distillation. A mild vacuum would be very useful for this. Do you have a more volatile solvent like methylene chloride rather than toluene?

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[*] posted on 10-7-2014 at 22:52


Toluene is not a good choice for the final extractions as it is terribly difficult to remove. I suggest you to rather form a stable salt (hydrochloride, oxalate, etc.). If you insist on isolating the free base, then first rotavap off the toluene (or whatever device you have to remove solvents), then add a more volatile solvent (methanol, MTBE, etc.) and evaporate under reduced pressure again, repeat one or two more times (this usually efficiently removes the toluene even from liquid products or amorphous solids).

The general indications for choosing an appropriate extraction solvent based on the properties of the compound can be found in this thread.
Quote: Originally posted by AvBaeyer  
You need to be careful about evaporating your solvent in air as diphenylhydramine, being an amine, will absorb CO2 giving you a relatively useless solid.

As far as I know, that does not occur with tertiary amines, since they cannot form the corresponding ammonium carbamates like the primary and secondary amines do.




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[*] posted on 17-7-2014 at 14:29


Use DCM to isolate the base and then wash the organic layer with water. Remove the DCM under reduced pressure or try to evaporate/boil it away. That would be the best course of action. Salts are a lot easier to work with than freebase amines.
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[*] posted on 24-2-2021 at 08:48


@OctanitroC - Did this ever work out? Curious what your results were, or if you chose a different procedure. You're right about the details on the properties of diphenhydramine being a little spotty on the internet. The sources I was able to find didn't have too much on its chemical properties or solubility in different solvents (other than water), and they seemed to be contradicting other sources.

P.S. - I apologize for reviving an old thread. I was just looking into some diphenhydramine extraction as well and found this thread. Thought it was better to revive an old relevant thread than to post a duplicate.
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